WO2010017265A2 - Injectable extended release compositions and methods of treating arthritis using same - Google Patents

Abstract

Provided herein are compositions, methods, and kits that include compositions suitable for intra- articular administration to a joint of a patient suffering from osteoarthritis and that include a biocompatible matrix; and at least one ion-channel regulator.

Description

INJECTABLE EXTENDED RELEASE COMPOSITIONS AND METHODS OF TREATING ARTHRITIS USING SAME

RELATED APPLICATIONS

[0001] This application claims priority to U.S.S.N 61/086,983, filed August 7, 2008, hereby incorporated by reference in its entirety.

BACKGROUND

[0002] Osteoarthritis is a primarily non-systemic, degenerative joint disease, the most common form of arthritis, and a leading cause of disability, affecting almost 21 million people in the US alone. Osteoarthritis is a degenerative disease that is typically characterized by one or more of progressive loss of articular cartilage, subchondral bone sclerosis, osteophyte formation, changes in the synovial membrane, and/or an increased volume of synovial fluid with reduced viscosity. Clinically, osteoarthritis can be characterized by joint pain, tenderness, limitation of movement, and progressive disability. Pain in osteoarthritis is localized and may be use-related, occurring during movement or weight-bearing. Joints most commonly affected include joints of the elbow, fingers, hips, knees, shoulder, wrist, spine and toes.

[0003] Available drugs for oral therapy include drugs for control of pain and inflammation, such as non-steroidal anti-inflammatory drugs (NSAID). However, NSAIDs have undesirable side effects which may include gastrointestinal bleeding or ulceration, fluid retention, and may lead to renal failure.

[0004] Arthritis may also be treated by topical analgesics and intraarticular injection of glucocorticoids and/or viscosupplements, but these treatments may provide only short term relief. There is an on-going need for effective treatments that provide long-term pain relief and/or a provides disease modifying properties.

[0005] Ion channels are glycoprotein structures located in the membrane of cells, including synovial cells and cartilage cells, which allow ions to pass through the membrane. Ion-channel regulators are a known group of agents that alter the entry of certain ions into or out of cells or cellular organelles, and are commonly used for a variety of conditions, e.g. cardiac conditions, and may be used for the treatment of arthritis. Such ion-regulators may provide relief from symptoms of osteoarthritis and decrease incidence of cartilage damage. For example, by affecting the entry of e.g. calcium ions into affected synovial cells, the calcium signaling pathway is disrupted, preventing the intracellular events that may culminate in inflammation and/or cartilage destruction. However, there is a need for formulations that provide long-term benefits of such therapy.

SUMMARY

[0006] Provided herein are extended release compositions suitable for intra- articular administration to a joint of a patient suffering from osteoarthritis, comprising a biocompatible and/or biodegradable matrix; and at least one ion-channel regulator in a amount effective to treat the osteoarthritis when administered by intra- articular injection. In some embodiments, a single administration of a dose of the composition may provide extended release of the ion- channel regulator into the joint over at least one day or more, Exemplary effective amounts of ion-channel regulators present in the disclosed composition include an amount effective to increase joint function/ and or an amount effective to decrease pain. Increased joint function and/or decrease pain may be ascertained using e.g., standard acceptable tests such as the WOMAC test, described below.

[0007] Ion channel regulators include one or more sodium ion channel regulators, calcium channel regulators, a potassium channel regulators, chloride channel regulators, and/or a connexon channel regulator, or combinations thereof. For example, a disclosed composition can include two ion channel regulators, e.g. two or more different calcium channel regulators, two or more different sodium channel regulators or a calcium channel regulator and a sodium channel regulator. Exemplary compositions may include about 1:1 by weight ratio of e.g., two different ion channel regulators, e.g. calcium-channel regulators, for example, verapamil and diltiazem. In some embodiments, compositions may further include a viscosupplement and/or steroid.

[0008] For example, provided herein is composition that includes therapeutic microspheres suitable for intra- articular injection and having a diameter of about 30 to about 60 microns, wherein the therapeutic microspheres comprise verapamil (or a pharmaceutically acceptable salt thereof) and a polymer chosen from polylactic acid or polylactic-co-glycolic acid. [0009] A single administration of the composition, when injected intraarticularly, may provide extended release of the ion-channel regulator over a time of at least 15 days, at least 1 month, at least 3 months, at least 6 months, or more.

[0010] Disclosed compositions can include a solvent, a pharmaceutically acceptable carrier or pharmaceutically excipient and/or a surfactant.

[0011] The biodegradable and/or biocompatible matrix may be, in some embodiments, substantially in the form of a microparticle or a nanoparticle. In another embodiment, the composition is substantially in the form of microspheres. Exemplary matrices may include a hydrogel, a liposome, or a polymer. Such polymers include polylactic acid, polyglycolide, poly(caprolactone), polyanhydrides, polyamines, polyorthoesters, polycarbonates, polyphosphoesters, polyesters, albumin, and copolymers and mixtures thereof.

[0012] Disclosed compositions may be flowable, for example, may be capable of administration by a 18 to 27 gauge needle.

[0013] The disclosed extended release compositions may increase joint function and/or decrease pain over a longer time period when administered to a patient intraarticularly as compared to a time period of increased joint function and/or decreased pain obtained by administering a composition comprising the same dosage of said ion-regulators without the biocompatible matrix.

[0014] Also contemplated herein are kits for use in treating osteoarthritis comprising a biocompatible polymer matrix, such as for example polylactic acid or polylactic -co- glycolic acid, disposed in a first container; one or more ion channel regulators ;a needle; and optionally instructions for use. For example, the first container may be a syringe. In some embodiments, one or more ion channel regulators are disposed in a second container, for example a syringe.

[0015] This disclosure also provides for a method of treating arthritis, e.g. osteoarthritis, in a patient in need thereof, comprising administering to a joint of the patient by intra- articular injection a disclosed extended release composition. DETAILED DESCRIPTION

[0016] The present disclosure is directed in part to extended or sustained release compositions suitable for intra-articular administration to a joint of a patient suffering from osteoarthritis. Such compositions may provide, upon, for example, a single administration of a dose of the composition to a joint of a patient, extended release of an ion-channel regulator effective to reduce symptoms of, or treat, arthritis, over the course of at least one day or more, without necessitating multiple administrations. The compositions and methods can be used to significantly increase the time period over which an effective dose of an ion-channel regulator is released and may increase the time over which e.g. symptoms can be abated.

[0017] Before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0018] The expression "extended release", or slow release, as used herein, includes, without limitation various forms of release, such as controlled release, timed release, sustained release, delayed release, long acting and immediate release that occurs with various rates.

[0019] The term "therapeutic effect" is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and/or conditions in an animal or human. The phrase "therapeutically-effective amount" means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. The therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. For example, certain compositions of the present invention may be administered in a sufficient amount to produce a at a reasonable benefit/risk ratio applicable to such treatment. [0020] A "patient," "subject" or "host" to be treated by the subject method may mean either a human or non-human animal.

[0021] The term "treating" is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disease.

[0022] The term "pharmaceutically acceptable excipient" is art-recognized and refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body. Each excipient must be "acceptable" in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials which may serve as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose and sucrose, and derivatives and/or polymers or co-polymers thereof; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) other excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

Compositions

[0023] In an embodiment, the disclosed compositions may be used for implantation, injection, or otherwise placed totally or partially within or adjacent to the intraarticular space of a joint of a patient, for example, a joint of a patient suffering from osteoarthritis. Compositions disclosed herein may be suitable for administration by injection through a needle into e.g. an intra-articular space, and may be isotonic, and/or may have a suitable pH to e.g., minimize possible side effects. Compositions disclosed herein, upon intra-articular injection, may result in minimal tissue irritation and may degrade in vivo into substantially non-toxic residues.

[0024] Disclosed herein are compositions that include one, two, or more ion-channel regulators and a biocompatible matrix. The ion-channel regulator(s) of the composition and the biocompatible and/or biodegradable matrix, e.g. a biocompatible and biodegradable polymer, may form a substantially homogeneous matrix, or the ion-channel regulator(s) may be encapsulated in some way within the matrix. For example, a matrix (e.g. a polymer) may be first encapsulated or formed in a microparticle or nanoparticle and then combined with an ion-channel regulator in such a way that at least a portion of the e.g., microparticle structure is maintained. In a different embodiment, the ion-channel regulator and matrix are combined and then formed into a micro- or nano-particle. Exemplary processes for making suitable microparticles is provided below.

[0025] Alternatively, the ion-channel regulator may be sufficiently immiscible in a matrix (e.g. a polymer) that it is dispersed as small droplets, rather than being dissolved, in the polymer. In some embodiments, regardless of the homogeneity of the composition, the release rate of the ion-channel regulator in vivo remains controlled, for example, at least partially as a function of hydrolysis of a matrix or polymer bond.

[0026] Exemplary compositions may be flowable and/or may be capable of administration by a 18 to 27 gauge needle, e.g., a 21 to 27 gauge needle suitable for intra- articular administration. For example, a composition may be capable of administration by a 21 gauge needle, a 24 gauge needle, a 25 gauge needle, and/or a 27 gauge needle.

[0027] A single administration of a dose of the composition may provide extended release, after one administration, of one or more ion-channel regulator(s) by at least one day, 10 days, 15 days, 1, 2, 3, 4, 5, 6 months or more, or even 1 year or more.

[0028] The matrix of the composition may be biocompatible and/or biodegradable, and are suitable for intra- articular injection. The matrix may comprise a polymer, hydrogel (e.g. a colloidal disperson of ion-channel regulator in water or an aqueous solution) liposomes, or the like. [0029] In some embodiments, a matrix of the contemplated composition comprises a biodegradable polymer. Biodegradable polymers differ from non-biodegradable polymers in that they can be degraded during in vivo therapy. This generally involves breaking down the polymer into its monomelic subunits. In principle, the ultimate hydrolytic breakdown products of a poly(phosphoester) are phosphate, alcohol, and diol, all of which are potentially non-toxic. The intermediate oligomeric products of the hydrolysis may have different properties, but the toxicology of a biodegradable polymer intended for implantation or injection, even one synthesized from apparently innocuous monomeric structures, is typically determined after one or more in vitro toxicity analyses.

[0030] A contemplated biodegradable polymer is preferably sufficiently pure to be biocompatible itself and remains biocompatible upon biodegradation. By "biocompatible" is meant that the biodegradation products or the polymer itself are non-toxic and result in only minimal tissue irritation when implanted or injected into vasculated tissue.

[0031] The release properties of a biodegradable polymer in vivo may depend upon its molecular weight, crystallinity, biostability, and the degree of cross -linking. In general, the greater the molecular weight, the higher the degree of crystallinity, and the greater the biostability, the slower biodegradation will be.

[0032] In some embodiments, the composition may include about 5 weight percent to about 90 weight percent polymer, or about 10 wt% to about 80 wt%, or about 15 wt% to about 60 wt %.

[0033] Polymers may be provided as copolymers, polymer blends, polymer alloys, or terpolymers, or polymers with more than three species of monomers. In certain embodiments, polymers are comprised almost entirely, if not entirely, of the same subunit. In other embodiments, the polymers may be copolymers, in which different subunits and/or other monomeric units are incorporated into the polymer.

[0034] In certain instances, the polymers are random copolymers, in which the different subunits and/or other monomeric units are distributed randomly throughout the polymer chain. In part, the term "random" is intended to refer to the situation in which the particular distribution or incorporation of monomeric units in a polymer that has more than one type of monomeric units is not directed or controlled directly by the synthetic protocol, but instead results from features inherent to the polymer system, such as the reactivity, amounts of subunits and other characteristics of the synthetic reaction or other methods of manufacture, processing or treatment.

[0035] The ratio of different subunits in, e.g. a co-polymer may vary. In some embodiments, polymers are effectively composed of two different subunits, in which the ratio of the subunits may vary from less than 1:99 to more than 99:1, or alternatively 10:90, 15:85, 25:75, 40:60, 50:50, 60:40, 75:25, 85: 15, 90: 10 or the like.

[0036] Polymers contemplated for use as matrix and in compositions provided herein include biocompatible, biodegradable polymers such as poly(alpha-hydroxy acid) polymers such as poly(lactic acid), poly(glycolic acid), copolymers of lactic acid and glycolic acid (PLGA), polyoxalates, polycaprolactone, copolymers of caprolactone and lactic acid, poly(ether ester) multiblock copolymers based on poly(ethylene glycol) and poly(butylene terephthalate), tyrosine-derived polycarbonates, poly(hydroxybutyrate), polydioxanone, poly(alkylcarbonate), poly(orthoesters), polyesters, poly(hydroxyvaleric acid), poly(malic acid), poly(tartaric acid), poly(amines), poly(acrylamides), polyphosphoesters, polyanhydrides, polyphosphazenes, and albumin. Suitable polymeric materials also include waxes such as glycerol mono-and distearate and the blends thereof. If a suitable polymer includes a hydrophilic end group such as carboxylic acid, which may be endcapped with a hydrophobic group including, but not limited to, lauryl esters or methoxy.

[0037] Exemplary biodegradable polymers include poly (alpha-hydroxy acid) polymers such as poly(lactic acid) (PLA), poly(glycolic acid(PGA), and copolymers of lactic acid and glycolic acid (PLGA). The lactic acid may be present in a range from about 1 wt. % to about 100 wt. % of the polymer, or from about 25 wt. % to about 75 wt. % of the polymer. The polymer may include a copolymer of lactic acid and glycolic acid. When lactic acid is present, the glycolic acid may be present in a range from about 35 wt. % to about 65 wt. % of the polymer. In other embodiments, the lactic acid is present in a range from about 45 wt. % to about 99 wt. % of the polymer. In some embodiments, the biodegradable polymer is a terpolymer of lactic acid, glycolic acid, and poly ε-caprolactone. In some embodiments, the biodegradable polymer is a terpolymer of 5 wt. % lactic acid, 55 wt. % glycolic acid, and 40 wt. % poly ε-caprolactone.

[0038] The composition may, in some embodiments, further include a solvent. For example, the matrix (e.g. polymer) and a solvent may form a stable homogenous emulsion or solution, to which the ion channel regulator can be mixed e.g. substantially before administration, or immediately before administration. Exemplary compositions may include about 5 wt % to about 50% wt solvent. Exemplary solvents contemplated for use in certain compositions include aromatic alcohols, lower alkyl esters of aryl acids, lower aralkyl esters of aryl acids, aryl ketones, aralkyl ketones, lower alkyl ketones, and lower alkyl esters of citric acid, and combinations thereof. In one embodiment, the solvent is selected from the group consisting of ethyl oleate, benzyl benzoate, ethyl benzoate, lauryl lactate, benzyl alcohol, lauryl alcohol, glycofurol, ethanol, tocopherol, polyethylene glycol, triacetin, a triglyceride, an alkyltriglyceride, a diglyceride, sesame oil, peanut oil, castor oil, olive oil, cottonseed oil, perfluorocarbon, N-methyl-pyrrolidone, DMSO, glycerol, oleic acid, glycofurol, lauryl lactate, perfluorocarbon, propylene carbonate, or mixtures thereof. Other exemplary contemplated solvents include methyl benzoate, ethyl benzoate, n-propyl benzoate, isopropyl benzoate, butyl benzoate, isobutyl benzoate, sec-butyl benzoate, tert-butyl benzoate, isoamyl benzoate, or benzyl benzoate. For example, the solvent may include benzyl benzoate and/or benzyl alcohol.

[0039] In certain compositions provided herein, the compositions may further include a surfactant. For example, the presence of a surfactant may induce an emulsion of a matrix/solvent blend, and may provide for easier injection. Exemplary surfactancts which may be used in certain contemplated compositions include ionic surfactants, nonionic surfactants or polymeric surfactants such as polysorbates, ethylene oxide/propylene oxide block copolymers, or ethylene glycol/propylene gycol block co-polymers.

[0040] In another embodiment, the composition may include microparticles or nanoparticles formed from a polymer, such as those biodegradable polymers discussed above. Such biocompatible and/or biodegradable microparticles of the present invention can be prepared by any known method and equivalents thereof that are capable of producing microparticles in a size range sufficiently effective for use in an injectable formulation or for delivery or infusion through a hypodermic needle or catheter. [0041] Methods for making microparticles include double emulsion/solvent evaporation, coacervation, and spray drying. For example, an emulsion/solvent evaporation process can include dissolving a suitable biodegradable and/or biocompatible polymer in an organic solvent, e.g. an oil, resulting in the organic phase. Suitable organic solvents for the polymeric materials include but are not limited to acetone, halogenated hydrocarbons such as chloroform and methylene chloride, aromatic hydrocarbons such as toluene, halogenated aromatic hydrocarbons such as methylene chloride, and cyclic ethers such as dioxane. The organic phase is then mixed with a non-solvent for the polymer such as an aqueous or silicone based solvent to form an emulsion. The emulsion is then mixed with a larger volume of the non- solvent. The micro or nano-particles are then collected and dried. Process parameters such as solvent and non-solvent selections, polymer/solvent ratio, temperatures, stirring speed, and dry cycles are adjustable to achieve the desired particle size, surface smoothness, and narrow particle size distribution. In some embodiments, a composition comprising such a microparticle can include a surfactants such as e.g., polyvinylalcohol which may be incorporated into the non-solvent. The use of such surfactants may to form microparticles with a smoother surface.

[0042] Microparticles may also be formed using a coacervation process which includes dissolving a suitable biodegradable polymer in an organic solvent resulting in an organic phase. Suitable organic solvents for the polymeric materials include but are not limited to acetone, halogenated hydrocarbons such as chloroform and methylene chloride, aromatic hydrocarbons such as toluene, halogenated aromatic hydrocarbons such as methylene chloride, and cyclic ethers such as dioxane. The organic phase is then mixed with a non-solvent for the polymer such as silicone-based solvent. For example, the non- solvent may be miscible with the organic solvent and the polymer may have a low solubility in the solvent. The non- solvent can cause the polymer to come out of solution in the form of a dispersed liquid phase comprising polymer droplets. The polymer droplets are then mixed with a hardening agent to form solid microparticles. T he microparticles are then collected and dried. Process parameters such as solvent and non-solvent selections, polymer/solvent ratio, temperatures, stirring speed, and dry cycles are adjustable to achieve the desired particle size, surface smoothness, and narrow particle size distribution. [0043] A spray drying process may also be used to form micro or nano-particles. This process includes dissolving a suitable biodegradable/biocompatible polymer in an organic solvent, such as listed above, and then spraying the solution through nozzles into a drying environment provided with sufficient elevated temperature and/or flowing air to effectively extract the solvent. Adding one or more surfactants such as e.g., sodium lauryl sulfate, polyoxyethylene sorbitan monoleate or triblock poly(ethylene oxide)/ (propylene oxide) (PPO) copolymers during this process, or as part of a composition comprising the formed micro or nanoparticles may, e.g., improve the surface smoothness of the microparticles.

[0044] The biodegradable microparticles or nanoparticles may be of various shapes including but not limited to spherical, pyramidal, cubical, cylindrical, rhombic, and other geometric shapes. The particle size range for such particles is preferably sufficient such that they are effectively injectable through, e.g. 18 to 27 gauge needle, for example, the microparticles may be about 5 to about 150 microns, about 10 to 100 microns, or about 35 to about 55 microns. In some embodiments, a combination of mean particle size ranges may provide a more long lasting effect such as, for example, a formulation that contains microparticles of a mean particle size range of 30 to 50 microns mixed with microparticles of a mean particle size range of 125 to 150 microns. It will be appreciated by those skilled in the art that the e.g., aqueous compositions of the present invention containing microparticles may be delivered to a treatment site by other conventional methods, including catheters, infusion pumps, pens devices and the like. The particle sizes of the microparticles would be adjusted correspondingly.

[0045] In certain embodiments, for example, when the composition includes microparticles, the composition may further include a carrier vehicle. Exemplary carrier vehicles include water and aqueous solutions of viscosity enhancers. Suitable viscosity enhancers include, but are not limited to, hyaluronic acid, modified hyaluronic acid, sodium hyaluronate, collagen, poly(alkylene oxide)-based polymers such as polyethylene glycol, chitosan, fucans, copolymers of polysaccharides with degradable polymers, gelatin, starch, cellulose, cellulose derivatives (e.g., regenerated cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate), casein, dextrans, polysaccharides, and any viscosupplement formulations. [0046] The ion channel regulators contemplated for use in the disclosed compositions include one, two or more of a calcium-channel regulator, a sodium-channel regulator, a potassium-channel regulators, chloride-channel regulators, cation-ion channel regulators, anion-ion channel regulators, non-selective ion channel regulators, mixed channel regulators, and connexon-channel regulators (i.e., chemical agents that regulate the movement of ions and molecules through connexons in synovial cells, which consist of the protein known as connexin 43). Calcium-, sodium-, potassium-, chloride-, cation- and anion-channel regulators respectively substantially regulate the movement of calcium ions, sodium ions, potassium ions, chloride ions, anions and cations through ion channels in the membranes of cells. Non- selective ion channels are ion channels that allow any combination of anions and cations to pass through the membranes of cells, and non-selective ion-channel regulators regulate the movement of those ions. Connexon-channel regulators regulate the movement of ions through connexons. Connexons are a class of ion channels consisting of the protein connexin 43, known to be present in synovial tissue and to occur in increased amounts in arthritic joints. For example, when two more ion channel regulators are included in a disclosed composition, such ion channel regulators may be chosen from for example two or more calcium-channel regulators, or for example one or more calcium channel regulator or sodium channel regulators.

[0047] Representative examples of calcium-channel regulators include amlodipine, bepridil, diltiazem hydrochloride, felodipine, gallopamil, isradipine, nicardipine, nifedipine, nimodipine, nitrendipine, verapamil, and mixtures thereof. Representative examples of sodium channel regulators include quinidine, encainide, mexitil, disopyramide, procainamide, tetrodotoxin, and mixtures thereof. Representative examples of potassium channel regulators include tedisamil, glibenclamide, dofetilide, amiodarone, azimilide, tolbutamide, propranolol, and mixtures thereof. Representative examples of chloride channel regulators include 5-Nitro- 2-(3-phenylpropylamino)benzoic acid, chlorotoxin, picrotoxin, and 9-Anthracenecarboxylic acid and mixtures thereof. A representative mixed channel regulator includes vernakalant.

[0048] Representative examples of connexon-channel regulators include lindane, octanol, 18α-glycyrrhetinic acid, calcium- ion concentration, pH, mimetic peptides, and certain antibodies. It is known that certain mimetic peptides can be used to block connexons and therefore may be suitable as connexon channel regulators in accordance with the present invention. For example, the synthetic tridecapeptide VCYDKSFPISHVR (residue numbers 63- 75), and the undecapeptide SRPTEKTIFII (residue numbers 204-214) are able to block connexin 43, as described in Leybaert, L., Braet, K., Vandamme, W., Cabooter, L., Martin, P. E. M. and Evans, W. H., "Connexin channels, connexin mimetic peptides and ATP release". Cell Commun. Adhesion. 10:251-257, 2003. Mimetic peptides consisting of 2 or more amino acids can similarly be formed employing any portion of the amino acid sequence of connexin 43, and the peptides may be effective, some more than others, in regulating the movement of ions through the connexon.

[0049] In some embodiments, a disclosed composition comprises about a 1:1 ratio by weight ratio of two different ion-channel regulators, or about a 1:1.5 ratio, about a 1:2 ratio of two different ion-channel regulators, or about a 1:3 ratio of two different ion-channel regulators, e.g. two different calcium ion-channel regulators. For example, a composition may comprise verapimil and diltiazem in e.g., a 1:1 ratio by weight.

[0050] In other embodiments, the compositions may include about 1%, 2%, 5% 10% weight percent of ion-channel regulator(s) (or a pharmaceutically acceptable salt thereof). For example, when the composition comprises micro or nanoparticles, such particles may comprise about 1%, about 2%, about 10% or more by weight, for example about 1 to about 20% (w/w) of ion-channel regulators.

[0051] Exemplary compositions disclosed herein may further include other osteoarthritis treatment agents, such as a viscosupplement. Viscosupplements include hylan, hyaluronic acid and other hyaluronan (sodium hyaluronate) compounds, which are natural complex sugars of the glycosaminoglycan family. Hyaluronan is a long-chain polymer containing repeating disaccharide units of Na-glucoronate-N-acetylglucosamine. Other osteoarthritis treatment agents that may be included in the compositions include non-steroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen, naproxen, and COX-2 inhibitors; analgesics such as aspirin and acetaminophen; glycans, including glucosamines, e.g. glucosamine sulfate and glucosamine hydrochloride; and proteoglycans, such as chondroitin compounds, as well as various other known narcotics, steroids, antibiotics, immunomodulators, penicillamine, and the like. [0052] Extended release compositions provided herein may locally (e.g. in or near an affected joint or related synovial space of a patient) provide sustained release of an ion-channel regulator. In some embodiments, compositions provide an initial burst release of an ion- channel regulator upon administration, e.g. for immediate biological action, and also provide further release of the ion-channel regulator to the administered joint over a time of at least one day, 15 days, 1 month, or more, as described above. For example, an initial burst of an ion- channel regulator after administration of a disclosed composition may reduce the symptoms of and/or treat osteoarthritis over a period of some time, e.g. one or two days, and the composition may then further release (e.g. with a substantially zero-order kinetic release profile) the ion-channel regulator and/or may continue to reduce the symptoms of and/or treat osteoarthritis over the period of time, e.g. about 1 to about 7 days, about 1 to about 30 days, or about 1 to about 180 days, or more. In other embodiments, extended release compositions disclosed herein may have a minimal burst release profile. For example, about 2.5 μg verapamil may be released from microparticles having verapamil (or its pharmaceutically acceptable salts thereof) per day over at least 21 days or more. Such microparticles may have an "initial burst" of for example about 3 μg verapamil.

[0053] Release profiles of the disclosed compositions may be modified by e.g. preparation techniques (e.g. preparation of microspheres), ratio of copolymers (e.g. ratio of poly(lactic acid)/poly(glycolic acid), and/or other components in the composition, e.g. surfactants.

[0054] A composition may increase joint function and/or decrease pain over a longer time period (e.g. about 1 day, about 1 week, about 1 day to about 30 days, about 1 day to about 6 months or more), as compared to a time period of increased joint function and/or decreased pain obtained by administering a composition comprising the same dosage of said ion- regulators without a biocompatible matrix.

[0055] Joint pain may be assessed indirectly or directly. Indirect measures of joint pain and/or joint function include static and dynamic weight-bearing, foot posture, and/or gait analysis including e.g. paw elevation time during walking, spontaneous mobility, and/or heat sensitivity. [0056] For example, measurements of weight bearing in animal models include analysis of weight distribution on two hind paws as a measure of the force exerted by each limb on a transducer plate in the floor over a given time period, with weight borne by each hind limb expressed e.g., as percent of body weight, percent of weight borne by both hind limbs, or the ratio or difference between each hind limb. A significant shift of weight from the arthritic site to the contralateral limb can be taken as a pain measure. Weight bearing and gait analysis are used for example in clinical settings as well.

[0057] Posture, range of motion gait analysis can be quantified in arthritis models using rating scales, e.g. by analyzing static (standing) and dynamic (walking) behaviors to calculate a pain score in animals and/or patients with joint arthritis.

[0058] Behavioral tests may also be used to ascertain pain by directly assessing mechanical sensitivity of a joint, e.g. a knee joint, by measuring hind limb withdrawal reflex threshold of knee compression force, struggle threshold angle of knee extension and/or vocalizations evoked by stimulation of the knee.

[0059] Clinically, patients can also be assessed for pain using patient self report questionnaires such as the Visual Analog Scale (VAS), McGiIl Pain Questionnaire (MPQ), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Health Assessment Questionnaire (HAQ), Medical Outcomes Study 36-item Short Form Health Survey (SF-36), and Disease Activity Score (DAS-28). For example, the WOMAC is one of the most commonly used measures of pain and/or physical disability (e.g. joint function) in patients with osteoarthritis of the hip and/or knee, with demonstrated reliability and validity in a range of patient groups. The WOMAC evaluates three dimensions (pain, stiffness and physical function) using a numeric rating scale or VAS. Typically, in addition to a sore of each subscale, an index score or global score is calculated.

[0060] Meniscal tears can also be evaluated, such as in a rat model. Evaluation of meniscal tear induced osteoarthritis lesion in rat knees may require division of the tibial plateau into 3 zones of equal width using e.g. an ocular micrometer, with zone 1 on the outside and zone 3 on the inside. Width of significant cartilage degeneration may represent extent of degeneration in which chondrocyte and/or proteoglycan loss extend through 50% or more of the original cartilage thickness. Collagen damage can be measured as the width of any collagen damage across the tibial plateau.

Methods

[0061] In one embodiment of the present invention, a method for treating osteoarthritis in a patient in need thereof comprises directly administering to the joint an effective amount of an extended release composition as disclosed herein. Administering the ion-channel regulator may be accomplished by direct (intraarticular) injection of a disclosed into an arthritic joint. Intraarticular injection of disclosed compositions may allow biologically sufficient concentrations of ion-channel regulator to be applied to the affected synovial tissue over a period of time without the risk of producing the undesirable side-effects that can occur as the result of a higher concentrations of ion-channel regulator that may be required by other administration techniques. Such injection techniques are known to those skilled in the art.

[0062] A method of increasing normal joint collagen in a patient in need thereof, for example, a patient suffering from osteoarthritis is also provided. For example, upon intra- articularly injecting a disclosed composition, normal collagen in an affected joint may increase by at least about 2%, about 5% or at least about 10%, as measured or assessed at about 1 week, 3 weeks, 1 month or more after e.g. one administration of a disclosed composition. In another embodiment, a method is provided to ameliorate cartilage degeneration in a joint of a patient in need thereof comprising administering intra- articularly a composition disclosed herein. For example, such a provided method may provide up to at least 5% or more, at least 10%, or at least 15% or more reduction in tibial and/or femoral cartilage degradation.

[0063] An effective dose or amount, and any possible affects on the timing of administration of the formulation, may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals (preferably at least 5 animals per group), or in human trials if appropriate. The effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment. Kits

[0064] Kits for use in treating arthritis are also contemplated. An exemplary kit may include a biocompatible polymer matrix, such as those disclosed herein (e.g., polylactic acid or polylactic -co- glycolic acid), wherein the polymer matrix is disposed in a first container and a one or more ion channel regulators. A needle may also be provided for ease of use. Optionally instructions for use are included within the kit.

[0065] In another embodiments, the one or more ion channel regulators are disposed in a second container. In some embodiments, the first container and/or the second container is a syringe.

[0066] The examples which follow are intended in no way to limit the scope of this invention but are provided to illustrate how to prepare and use compounds of the present invention. Many other embodiments of this invention will be apparent to one skilled in the art.

EXAMPLES

EXAMPLE 1

[0067] Verapamil and poly (lactic acid)/poly (glycolic acid) with molar compositions from 100/0 to 50/50 lactic/gly colic acid and average molecular weights of about 10,000 g/mol to about 100,000 g/mol are dissolved in methylene chloride/acetic acid and the mixture is dropped slowly into an aqueous PVA solution and additional agitation is performed. The suspension is transferred into aqueous PVA solutions and the organic solvents are removed by agitation until microspheres are solidified. The hardened microspheres are centrifuged and washed with deionized water, and freeze-dried.

EXAMPLE 2 In-Vitro Release

[0068] A 2-ml phosphate buffer solution is added into a 5-ml tube and 10 mg of verapamil loaded microspheres are added to the tube and suspended thoroughly. The tube is placed in a 50 ⁰C water bath and shaken at 160 rpm horizontally. At different time intervals, the tube is centrifuged at 3500 rpm for 10 min and a 2-ml supernatant is removed to be analyzed and the equal volume of fresh phosphate buffer is re-added. The released ion-channel regulator is assayed by spectrophotometry on a fluorescence spectrometer. EXAMPLE 3 In-Vivo Animal Model

[0069] A rat study was conducted to determine the efficacy of slow release verapamil loaded microspheres given by intra-articular injection as compared to single and multiple verapamil dosing (without any slow release) in meniscal tear induced osteoarthritis. Rats were administered a slow release verapamil composition once on day 4 (slow release CR-A) vs. verapamil (Verapamil IX: 3μg verapamil HCl in a 40 ul saline suspension) injected intra- articularly on day 4 or given 6 times (3μg verapamil HCL in a 40 ul saline suspension) on days 4, 8, 12, 16 and 24 for 4 weeks. Groups of 5 rats each (without surgery) had slow release formulations injected into both knees, on day 4 (right knee and day 25 (left knee), for evaluation of irritancy. The slow release verapamil composition (CR-A) was verapamil HCl encapsulated into 50 micron microspheres of poly-lactate/polyglycolate (50:50 mole ratio, having a weight average molecular weight of 5OkDa) in a 40 ul saline suspension. The microspheres release approximately 2.5ug verapamil per day over 21 days with an initial 3 ug burst.

[0070] Male Lewis rats at 250-275 (Charles River #7616552), weighing approx. 275-300 grams at start were used.

[0071] Animals (15/group for surgery housed 5/cage, were randomized to groups based on body wt after at least 2 days acclimation and anesthetized with isoflurane and the right knee area prepared for surgery. A skin incision was made over the medial aspect of the knee and the medial collateral ligament exposed by blunt dissection, and then transected. The medial meniscus was cut through the full thickness to simulate a complete tear. The skin was closed with suture. Dosing of CR-A was given by the intra-articular route (40 μl) and was performed on day 4 post-surgery (CR-A Group). The control for the CR-A group received saline on day 4. The control animals for the verapamil group received saline on days 4, 8,12,16,20,24. The verapamil IX Group received verapamil on day 4 and saline all other days (8,12,16, 20 and 24) and Verapamil 6X Group received verapamil on days 4, 8, 12,16, 20 and 24. All groups were terminated 4 weeks post-surgery (day 28).

[0072] Following 4-6 days in 5% formic acid decalcifier, the operated joints are cut into 2 approximately equal halves in the frontal plane and embedded in paraffin. Three sections are cut from each knee at approximately 150 μm steps and stained with toluidine blue. Right and Left knees from normal injected rats (animals 1-5 of groups 7 and 9) have a single section prepared and stained with T. Blue and are evaluated for general pathology changes. A total of (105x3+20 normal) toluidine blue sections were prepared.

[0073] All 3 sections of each knee are analyzed microscopically. In scoring the 3 sections, the worst-case scenario for the 2 halves on each slide is determined for general cartilage degeneration, proteoglycan loss, collagen damage, and osteophyte formation. The values for each parameter is then averaged across the 3 sections to determine overall subjective scores. In addition, for some parameters, regional differences across the tibial plateau were taken into consideration by dividing each section into 3 zones (1 -outside, 2-middle, 3-inside). In the surgical OA model, the outside (zl) and middle (z2) thirds are most severely affected, and milder changes are present on the inside third (z3). When zones are scored individually, scores were assigned based on % area of the zone affected. Zone areas are delineated using an ocular micrometer.

[0074] The following parameters are measured and/or scored:

[0075] General cartilage degeneration includes the important parameters of chondrocyte death/loss, proteoglycan loss, and collagen loss or fibrillation. Cartilage degeneration in the tibia is scored none to severe (numerical values 0-5) for each zone (area defined by micrometer) using the following criteria: 0=no degeneration; l=minimal degeneration, chondrocyte and proteoglycan loss, generally without fibrillation involving the mainly the superficial zone or extending into the upper 10% of the cartilage thickness (50% or greater width of the zone), or at least 5% but not more than 10% overall total proteoglycan and cell loss in the zone if lesion is focal and deeper in some areas; 2= mild degeneration, chondrocyte and proteoglycan loss with fibrillation involving mainly the upper 25% of cartilage thickness (50% or greater width of the zone), fibrillation generally superficial (upper 10%) while chondrocyte and PG loss extend into approximately 25% of the cartilage depth, or 10-25% overall chondrocyte and proteoglycan loss in the zone if lesion is focal and deeper in some areas; 3=moderate degeneration, chondrocyte and proteoglycan loss with fibrillation extending well into the midzone and generally affecting Vi (50%) of the total cartilage thickness (50% or greater width of the zone), fibrillation/collagen damage generally extends into upper 25% while chondrocyte and PG loss extend through 50% thickness, or 25-50% overall chondrocyte and proteoglycan loss in the zone if lesion is focal and deeper in some areas; 4=marked degeneration, chondrocyte and proteoglycan loss with fibrillation extending through the mid zone into the lower 1/3 (75% of cartilage thickness) but without complete (to the tidemark) loss of chondrocytes or proteoglycan (50% or greater width of the zone), fibrillation/collagen damage generally extend through the mid zone (50% thickness) but deep zone collagen remains intact and chondrocyte and PG loss extend through 75% of cartilage thickness, or 50- 75% overall chondrocyte and proteoglycan loss in the zone if lesion is focal and deeper in some areas; 5=severe degeneration, matrix loss to tidemark (75% or greater width of the zone), or 75-100% overall chondrocyte and proteoglycan loss in the zone

[0076] A 3-zone sum for cartilage degeneration is also calculated. Femoral general cartilage degeneration is scored using the same criteria without attention to zones.

[0077] Collagen matrix damage is scored separately in order to identify more specific effects. Collagen damage across the medial tibial plateau (most severely affected section of the 2 halves) is quantified by measuring the total width of the following: -Any damage (fibrillation ranging from superficial to full thickness loss)

-Severe damage (total or near total loss of collagen to tidemark, >90% thickness) -Marked damage (extends through 61-90% of the cartilage thickness) -Moderate damage (extends thru 31-60% of the cartilage thickness) -Mild damage (extends through 11-30% of the cartilage thickness) -Minimal damage (very superficial, affecting upper 10% only)

[0078] In addition to the above subjective general cartilage scoring, 2 cartilage degeneration width measurements are taken:

[0079] Total Tibial Cartilage Degeneration Width (μm) is a micrometer measurement of total extent of tibial plateau affected by any type of degeneration (cell loss, proteoglycan loss or collagen damage). This measurement extends from the origination of the osteophyte with adjacent cartilage degeneration (outside 1/3) across the surface to the point where tangential layer and underlying cartilage appear histologically normal. [0080] Significant Cartilage Degeneration Width (μm) reflects areas of tibial cartilage degeneration in which both chondrocyte and proteoglycan loss extend through greater than 50% of the cartilage thickness. In general, the collagen damage is mild (25% depth) or greater for this parameter but chondrocyte and proteoglycan loss extend to at least 50% or greater of the cartilage depth.

[0081] A micrometer depth of any type of lesion (both chondrocyte and proteoglycan loss, but may have good retention of collagenous matrix and no fibrillation), expressed as a ratio of depth of changed area vs. depth to tidemark, is taken in the area of greatest lesion severity in each of the 3 zones across the tibial surface at the midpoint of the zone. This measurement is the most critical analysis of any type of microscopic change present. The denominator can serve as an average measure of cartilage thickness in each of the 3 zones for comparison of anabolics when measures are taken at the midpoint of the zone.

[0082] Scoring of the osteophytes and categorization into small, medium and large is done with an ocular micrometer. Marginal zone proliferative changes have to be >200 μm in order to be measured and designated as osteophytes. Scores are assigned to the largest osteophyte in each section (typically found in the tibia) according to the following criteria: l=small up to 299 μm; 2=moderate 300-399 μm; 3=large 400-499 μm; 4=very large 500-599; 5=very large >600

The actual osteophyte measurement (tidemark to furthest distance point extending toward synovium) is also recorded.

[0083] The femoral cartilage degeneration score and the 3-zone sum of the tibial cartilage degeneration scores (mean of 3 levels) are summed to create a total cartilage degeneration score. The mean osteophyte score for each joint is added to this value to create a Total Joint Score-

Image analysis [0084] In order to quantitate and compare the cartilage matrix preservation, cartilage area measurements are taken from the most severely affected section of each animal. Photomicrographs are taken with a CoolSNAP-Pro microscope camera, and loaded into ImagePro Plus software. The following measurements are taken from tracings of these photomicrographs: total area from the tidemark to the surface (or projected surface in degenerated areas) over 9 cm (photomicrograph) of the tibial plateau, measured from the inner edge of the osteophyte; area of non-viable matrix (cartilage with less than 50% chondrocytes, proteoglycan, and intact collagen) and no matrix within the total area; and area of no matrix within the total area. The area of non- viable matrix is subtracted from the total area to get the area of viable matrix, and the area of no matrix is subtracted from the total area to get the area of any matrix (collagen matrix with or without chondrocytes and proteoglycan). These two values are then compared back to the total area to derive the % viable area and the % any matrix, which are compared between groups. Five left knees from the vehicle group are included in this process as normal controls.

[0085] Proteoglycan loss may be measured by the use of the saturation measure in ImagePro Plus. The total area (see description above) is traced, and the mean color saturation value is taken. This value is compared to the saturation of the normal controls to get the Proteoglycan Staining Intensity (Percent Loss) in the total area. In order to minimize the impact of natural variation in normal staining intensity, this process is repeated for the outer half of the tibial plateau. Synovial reaction, if abnormal, is described (e.g. fibrosis) and characterized with respect to inflammation type and degree but is not included in the score.

[0086] Damage to the calcified cartilage layer and subchondral bone (worst case scenario for all sections) is scored using the following criteria: O=No changes; l=Increased basophilia at tidemark, no fragmentation of tidemark, no marrow changes or if present minimal and focal; 2=Increased basophilia at tidemark, minimal to mild focal fragmentation of calcified cartilage of tidemark, mesenchymal change in marrow involves 1/4 of total area but generally is restricted to subchondral region under lesion; 3=Increased basophilia at tidemark, mild to marked focal or multifocal fragmentation of calcified cartilage (multifocal), mesenchymal change in marrow is up to 3/4 of total area, areas of marrow chondrogenesis may be evident but no major collapse of articular cartilage into epiphyseal bone (definite depression in surface); 4=Increased basophilia at tidemark, marked to severe fragmentation of calcified cartilage, marrow mesenchymal change involves up to 3/4 of area and articular cartilage has collapsed into the epiphysis to a depth of 250 μm or less from tidemark (e.g. definite depression in surface cartilage); 5=Increased basophilia at tidemark, marked to severe fragmentation of calcified cartilage, marrow mesenchymal change involves up to 3/4 of area and articular cartilage has collapsed into the epiphysis to a depth of greater than 250 μm from tidemark. Results

[0087] Slow release verapamil (CR-A; 3ug burst and 2.5ug/d for 21 days) was more effective than verapamil given once(3ug) or 6 times (3ug days 4,8,12,16,20,24) in a rat osteoarthritis model in reducing cartilage loss (all three measures A-D) compared to verapamil given once (VlX) or six times (V6X). Results are shown in Table 1. CR-A reduced tibial cartilage degradation width by 13% versus minimal effect by non-controlled release verapamil. Severe and marked collagen degradation was reduced by 17% with CR-A and actually increased with VlX and V6X. In addition, normal collagen width increased significantly with CR-A (protective effect) and decreased minimally with VlX and V6X.

TABLE 1 *P< 0.05

EXAMPLE 4 [0088] Assessment of pain and function of the joint of a patient is made prior to treatment, and at various times after treatment, using the visual analog scale (VAS) for pain, and the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, which assesses pain, function and stiffness in arthritic joints. A more detailed description of the nature and use of these clinical endpoints is given in "Clinical Development Programs for Drugs, Devices, and Biological Products Intended for the Treatment of Osteoarthritis, U.S. Dept. of Health and Human Services, Food and Drug Administration, July 1999", which is incorporated by reference herein.

[0089] Immediately after the initial VAS and WOMAC measurements are made, the patient's right knee is injected with a composition as disclosed herein including the calcium- channel regulator verapamil using the following basic injection procedure.

[0090] The patient is seated in a standard dental chair, with the knee flexed between 30-40 degrees. The knee is prepared with a sterile prep of betadine. Ethyl chloride spray provides skin anesthesia for the injection of 1% plain Xylocaine, which is injected into the skin and subcutaneous tissue. Precaution is taken not to inject any fluid into the knee. The patient is cautioned that although the majority of pain will be obviated, there will be some pain as the needle passes through the synovial lining. After enough time has elapsed to achieve effective local anesthesia, it is often useful to activate a fluoroscopy unit in the lateral position to obtain a view of the patella and contact zone of the femoral condyle with the tibial plateau. The point of insertion for the 21 -gauge injection needle is then chosen utilizing the lateral view of the knee and referencing the point of a standard anterolateral arthroscopy portal. The injection site is proximal to the normal portal site by some 1 to 1.5 centimeters. Using this as a guide, the needle is advanced inwardly to the intraarticular space just at the anterior contact point of the femoral condyle and the tibial plateau.

[0091] At one week intervals after injection, the patient is assessed using the VAS and WOMAC scoring as described above.

References

[0092] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0093] US2006/0269579; U.S.S.N. 60/975355, filed Sept. 26, 2007. Equivalents

[0094] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0095] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

[0096] What is claimed is :

Claims

L A extended release composition suitable for intra- articular administration to a joint of a patient suffering from osteoarthritis, comprising a) a biocompatible matrix; and b) at least one ion-channel regulator in a amount effective to treat the osteoarthritis when administered by intra- articular injection; wherein a single administration of a dose of the composition provides extended release of the ion-channel regulator into the joint over at least one day.

2. The composition of claim 1, wherein the matrix is biodegradable.

3. The composition of claims 1 or 2, wherein the amount effective to treat the osteoarthritis is an amount effective to increase joint function.

4. The composition of anyone of claims 1-3, wherein the amount effective to treat the osteoarthritis is an amount effective to decrease pain.

5. The composition of any one of claims 1-4, wherein the at least one ion channel regulator is chosen from: a sodium ion channel regulator, a calcium channel regulator, a potassium channel regulator, a chloride channel regulator, or a connexon channel regulator, or combinations thereof.

6. The composition of any one of claims 1-4, wherein the at least one ion channel regulator comprises two ion channel regulators.

7. The composition of claim 6, wherein the composition comprises two or more different calcium channel regulators.

8. The composition of claim 6, wherein the composition comprises two or more different sodium channel regulators.

9. The composition of claim 6, wherein the composition comprises a calcium channel regulator and a sodium channel regulator.

10. The composition of any one of claims 1-9, wherein the composition comprises a calcium channel regulator selected from the group consisting of amlodipine, bepridil, diltiazem hypochloride, felodipine, gallopamil, isradipine, nicardipine, nifedipine, nimodipine, nitrendipine, verapamil, and mixtures thereof.

11. The composition of any one of claims 1-10, wherein the composition comprises a sodium channel regulator selected from the group consisting of quinidine, encainide, mexitil, disopyramide, procainamide, tetrodotoxin, and mixtures thereof.

12. The composition of any one of claims 1-11, wherein a single administration of the composition provides extended release of the ion-channel regulator over a time of at least 15 days.

13. The composition of any one of claims 1-12, wherein a single administration of the composition provides extended release of the ion-channel regulator over a time of at least 1 month.

14. The composition of any one of claims 1-13, wherein a single administration of the composition provides extended release of the ion-channel regulator over a time of at least 3 months.

15. The composition of any one of claims 1-14, wherein a single administration of the composition provides extended release of the ion-channel regulator over a time of at least 6 months.

16. The composition of any one of claims 8-15, wherein the composition comprises about 1:1 by weight ratio of two different ion-channel regulators.

17. The composition of claim 7, wherein the composition comprises about 1 : 1 by weight ratio of two different calcium-channel regulators.

18. The composition of claim 16 or 17, wherein the composition comprises verapamil and diltiazem, or a pharmaceutically acceptable salt thereof.

19. The composition of any one of claims 1-18, wherein the composition further comprises a solvent.

20. The composition of any one of claims 1-19, wherein the composition further comprises a surfactant.

21. The composition of any one of claims 1-18, wherein the matrix is substantially in the form of a microparticle or a nanoparticle.

22. The composition of any one of claims 1-18, wherein the composition is substantially in the form of microspheres.

23. The composition of any one of claims 1-20, wherein the composition is flowable.

24. The composition of claim 22, further comprising a pharmaceutically acceptable excipient.

25. The composition of any one of claims 1-24, wherein the composition is capable of administration by a 18 to 27 gauge needle.

26. The composition of any one of claims 1-24, wherein the matrix is a hydrogel or a liposome.

27. The composition of any one of claims 1-24, wherein the matrix is a polymer.

28. The composition of claim 27, wherein the polymer is chosen from polylactic acid, polyglycolide, poly(caprolactone), polyanhydrides, polyamines, polyorthoesters, polycarbonates, polyphosphoesters, polyesters, albumin, and copolymers and mixtures thereof.

29. The composition of any one of claims 1-20, wherein the ion-channel regulator is about 2 to about 50 wt. % of the composition.

30. The composition of any one of claims 1-29, further comprising a visco supplement.

31. The composition of any one of claims 1-30 further comprising a steroid.

32. The composition of any one of claims 1-31, wherein said composition increases joint function and/or decreases pain over a longer time period when administered to a patient as compared to a time period of increased joint function and/or decreased pain obtained by administering a composition comprising the same dosage of said ion-regulators without the biocompatible matrix.

33. The composition of any one of claims 1-32, wherein said composition increases normal collagen width and/or decreases cartilage degradation when administered to a patient as compared to any collagen or cartilage change obtained by administering to a patient a composition comprising the same dosage of said ion-regulators without the biocompatible matrix.

34. A composition comprising therapeutic microspheres suitable for intra- articular injection and having a diameter of about 30 to about 60 microns, wherein said therapeutic microspheres comprise verapamil or a pharmaceutically acceptable salt thereof and a polymer chosen from polylactic acid or polylactic-co-glycolic acid.

35. A method of treating arthritis in a patient in need thereof, comprising administering to a joint of the patient by intra- articular injection a composition of any one of claims 1-34.

36. The method of claim 37, wherein the arthritis is osteoarthritis.

37. A method of increasing normal joint collagen in a patient suffering from osteoarthritis in one or more joints, comprising intra- articularly injecting a composition capable of releasing an ion-channel regulator substantially continuously over at least one week into said joint, wherein the composition comprises an ion-channel regulator and biodegradable, biocompatible polymer chosen from poly(lactic) acid or poly lactic-co glycolic acid.

38. The method of claim 37, wherein the normal joint collagen is increased by at least about 5%.